Matrix metalloproteinase-9 from bone marrow-derived cells contributes to survival but not growth of tumor cells in the lung microenvironment
Matrix metalloproteinase-9 from bone marrow-derived cells contributes to survival but not growth of tumor cells in the lung microenvironment
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DOI：
10.1158/0008-5472.can-05-2502
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发表时间：
2006-01-01
期刊：
影响因子：
11.2
通讯作者：
Matrisian, LM
中科院分区：
文献类型：
--
作者：
Acuff, HB;Carter, KJ;Matrisian, LM
在野生型和MMP-9、MMP-7或MMP-2缺失小鼠的实验转移测定中分析了特异性基质源性基质金属蛋白酶（MMP）的作用。MMP-9缺失小鼠显示刘易斯肺癌肿瘤数量减少81%，而MMP-7缺失小鼠显示肿瘤数量增加42%，并且与野生型对照相比，MMP-2缺失小鼠的肿瘤数量没有差异。同样，在原位肺癌模型中，与对照小鼠相比，MMP-9缺失小鼠能够在肺中建立肿瘤的数量减少了50%，尽管肿瘤的大小没有差异。MMP-9对肺肿瘤定殖的作用依赖于来自骨髓源性细胞的MMP-9的表达，并且最可能由中性粒细胞贡献。为了检查基质MMP-9的时间效应，来自表达人肺癌来源的A549细胞的生物发光成像显示，与对照小鼠相比，MMP-9缺失小鼠的肺中早在注射后19小时就有更少的肿瘤细胞，随后的生长速率没有差异。注射肿瘤细胞后6小时，MMP-9缺失小鼠与对照小鼠相比，发生凋亡的肿瘤细胞百分比增加了4倍。我们的结论是，MMP-9从骨髓有助于早期生存和建立在肺肿瘤，并没有影响随后的增长。这些结果为NIMP抑制剂在晚期肺癌患者临床试验中的失败提供了见解。
The role of specific stromal-derived matrix metaloproteinases (MMPs) was analyzed in experimental metastasis assays in wild-type and either MMP-9, MMP-7, or MMP-2 null mice. MMP-9 null mice showed an 81% reduction in Lewis lung carcinoma tumor number, whereas MMP-7 null mice showed a 42% increase in tumor number, and there was no difference in tumor number in MMP-2 null mice compared with wild-type controls. Similarly, in an orthotopic model of lung cancer, 50% fewer MMP-9 null mice were able to establish tumors in the lung compared with control mice, although the size of the tumors was not different. The effect of MMP-9 on lung tumor colonization was dependent on the expression of MMP-9 from bone marrow-derived cells and is most likely contributed by neutrophils. To examine temporal effects of stromal MMP-9, bioluminescence imaging from luciferase-expressing human lung cancer-derived A549 cells revealed that there were fewer tumor cells in the lungs of MMP-9 null mice as early as 19 hours after injection compared with control mice, with no difference in subsequent growth rates. Six hours after injection of tumor cells, MMP-9 null mice showed a 4-fold increase in the percent of tumor cells undergoing apoptosis compared with control mice. We conclude that MMP-9 from the bone marrow contributes to the early survival and establishment of tumors in the lung and has no effect on subsequent growth. These results provide insights into the failure of NIMP inhibitors in clinical trials in patients with late-stage lung cancer.